PROJECT SUMMARY/ABSTRACT Cancers are serious and highly prevalent diseases, with an estimated 14 million new cases and 8.2 million deaths worldwide in 2012. Among the wide variety of chemotherapeutic agents, taxane drugs like paclitaxel (Taxol) have emerged as standards of care for the treatment of certain cancers. Unfortunately, the utility of these drugs is limited by their pronounced lipophilicity and the recent emergence of resistant cancers, creating an urgent need for novel taxane chemotherapeutics. This proposal describes a plan to synthesize the taxane molecule taxagifine, as well as structurally related natural and unnatural taxanes, in an effort to provide new compounds for biological study. Taxagifine exhibits promising microtubule-stabilizing and cytotoxic properties and demonstrates potential activity against resistant cancers, but differs structurally from paclitaxel at several positions, including an unusual C17?C12 oxo-bridge functionality which will likely impart increased aqueous solubility relative to paclitaxel. Further studies of taxagifine have been frustrated by a lack of material: isolation from nature is extremely inefficient, and the C17?C12 oxo-bridge poses a significant challenge to any semi-synthetic routes. This proposal describes the first total synthetic approach to taxagifine and related compounds, with the hypothesis that the expansion of Sarpong's C?C activation/arylation reaction of carvone-derived cyclobutanols will enable a concise, convergent, and scalable synthesis of taxagifine. The Specific Aims of the proposal are: 1) Expansion of the C?C activation/arylation methodology recently developed by Sarpong and co-workers to allow for the use of synthetically versatile vinyl electrophiles, 2) Apply the C?C activation/vinylation reaction developed in Aim I to the construction of the oxo-bridged A ring and subsequently the total synthesis of taxagifine, and 3) Use the concise route to taxagifine developed in Aim II to make other natural taxanes containing the C17?C12 oxo-bridge, as well as unnatural taxagifine derivatives for structure-activity- relationship (SAR) studies. Our syntheses of unnatural analogs will focus on exploiting the synthetic route to install functionalization at underexplored positions on the taxagifine framework. The synthesis of paclitaxel- taxagifine hybrids will also be investigated to probe the taxagifine binding conformation. The development of a C?C activation/vinylation reaction will allow for the construction of a diverse array of terpenoid scaffolds, with potential use in medicinal chemistry and natural products total synthesis. Use of this reaction to synthesize taxagifine as well as natural and unnatural analogs will enable SAR and mechanism of action studies, furthering our understanding of microtubule-interactions and helping to identify potential second generation taxane therapeutic agents.